mPEG-NH2/2-FPBA/TubA exerts anti-hepatocellular carcinoma activity by targeting ABCF1-K430la through the KDM3A-H3K9me2-HIF1A axis.

Few systematic investigations have explored the use of polymeric micelles for the delivery of lactylated proteomic-modified drugs. A small-molecule drug Tubuloside A (TubA), which targets lactate modified at lysine 430 of ABCF1 and effectively inhibits hepatocellular carcinoma (HCC) progression, was identified in previous study. In this study, we selected a nanomaterial, mPEG-NH2+ 2-FPBA, as a drug carrier, which not only efficiently encapsulated the drug, but also facilitated targeted release within tumor tissues. The synthesized nanomicelle, mPEG-NH2/2-FPBA/TubA, can encapsulate drugs and release them under acidic conditions, making it well-suited for the acidic microenvironment characteristic of solid tumors. These micelles can penetrate the tumor region due to their enhanced permeability and retention (EPR) effects, traverse the cellular membrane, and release their payload intracellularly to maximize therapeutic efficacy. Both in vivo and in vitro experiments demonstrated that mPEG-NH2/2-FPBA/TubA effectively delivered TubA, resulting in a significant reduction in tumor growth; decreased expression of KDM3A, HIF1A, and Ki67; and an increase in H3K9me2 levels. This study presents an effective material delivery strategy for lactylated proteomic nanoparticles and elucidated their mechanism of action.